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TAFINLAR (dabrafenib) capsule

2013-12-08 11:56:28 来源: 作者: 【大中小】浏览:550次评论:0条

HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use TAFINLAR safely and effectively. See full prescribing information for TAFINLAR.
TAFINLAR(dabrafenib) capsules for oral use
Initial U.S. Approval: 2013
INDICATIONS AND USAGE
TAFINLAR is a kinase inhibitor indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test. (1, 2.1)
Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma. (1, 5.2)
DOSAGE AND ADMINISTRATION
•
Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR. (2.1)
•
The recommended dose is 150 mg orally twice daily taken at least 1 hour before or at least 2 hours after a meal. (2.2)
DOSAGE FORMS AND STRENGTHS
Capsules: 50 mg, 75 mg. (3)

CONTRAINDICATIONS
•
None. (4)
WARNINGS AND PRECAUTIONS
•
New Primary Cutaneous Malignancies: Perform dermatologic eva luations prior to initiation of therapy, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR. (5.1)
•
Tumor Promotion in BRAF Wild-Type Melanoma: Increased cell proliferation can occur with BRAF inhibitors. (5.2)
•
Serious Febrile Drug Reactions: Withhold TAFINLAR if fever ≥101.3ºF or complicated fever occurs. (5.3)
•
Hyperglycemia: Monitor serum glucose levels in patients with pre-existing diabetes or hyperglycemia. (5.4)
•
Uveitis and Iritis: Monitor patients routinely for visual symptoms. (5.5)
•
Glucose-6-Phosphate Dehydrogenase Deficiency: Closely monitor for hemolytic anemia. (5.6)
•
Embryofetal Toxicity: Can cause fetal harm. Advise females of reproductive potential of potential risk to a fetus. TAFINLAR may render hormonal contraceptives less effective and an alternative method of contraception should be used. (5.7, 8.1)
ADVERSE REACTIONS
Most common adverse reactions (≥20%) for TAFINLAR are hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
•
Concurrent administration of strong inhibitors of CYP3A4 or CYP2C8 is not recommended. (7.1)
•
Concurrent administration of strong inducers of CYP3A4 or CYP2C8 is not recommended. (7.1)
•
Drugs that increase gastric pH may decrease dabrafenib concentrations. (7.1)
•
Concomitant use with agents that are sensitive substrates of CYP3A4, CYP2C8, CYP2C9, CYP2C19, or CYP2B6 may result in loss of efficacy of these agents. (7.2)
USE IN SPECIFIC POPULATIONS
•
Nursing Mothers: Discontinue drug or nursing. (8.3)
•
Females and Males of Reproductive Potential: Advise female patients to use highly effective contraception during treatment and for 4 weeks following discontinuation of treatment. Advise male patients of potential risk for impaired spermatogenesis. (8.6)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 05/2013
Back to Highlights and Tabs
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 Patient Selection
2.2 Recommended Dosing
2.3 Dose Modifications
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 New Primary Cutaneous Malignancies
5.2 Tumor Promotion in BRAF Wild-Type Melanoma
5.3 Serious Febrile Drug Reactions
5.4 Hyperglycemia
5.5 Uveitis and Iritis
5.6 Glucose-6-Phosphate Dehydrogenase Deficiency
5.7 Embryofetal Toxicity
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
7 DRUG INTERACTIONS
7.1 Effects of Other Drugs on Dabrafenib
7.2 Effects of Dabrafenib on Other Drugs
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Females and Males of Reproductive Potential
8.7 Hepatic Impairment
8.8 Renal Impairment
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.2 Animal Toxicology and/or Pharmacology
14 CLINICAL STUDIES
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
*
Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

TAFINLAR® is indicated for the treatment of patients with unresectable or metastatic melanoma with BRAF V600E mutation as detected by an FDA-approved test.

Limitation of use: TAFINLAR is not indicated for treatment of patients with wild-type BRAF melanoma [see Warnings and Precautions (5.2)].

2 DOSAGE AND ADMINISTRATION

2.1 Patient Selection

Confirm the presence of BRAF V600E mutation in tumor specimens prior to initiation of treatment with TAFINLAR [see Warnings and Precautions (5.2)]. Information on FDA-approved tests for the detection of BRAF V600 mutations in melanoma is available at http://www.fda.gov/CompanionDiagnostics.

2.2 Recommended Dosing

The recommended dose for TAFINLAR is 150 mg orally taken twice daily, approximately 12 hours apart, until disease progression or unacceptable toxicity occurs. Take either at least 1 hour before or at least 2 hours after a meal [see Clinical Pharmacology (12.3)].

A missed dose can be taken up to 6 hours prior to the next dose. Do not open, crush, or break TAFINLAR capsule.

2.3 Dose Modifications

For New Primary Cutaneous Malignancies: No dose modifications are recommended.

Table 1. Recommended Dose Modifications for TAFINLAR
Target Organ	Adverse Reactionsa	Dose Modification
Febrile Drug Reaction	• Fever of 101.3ºF to 104°F	Withhold TAFINLAR until adverse reaction resolves. Then resume TAFINLAR at same dose or at a reduced dose level (see Table 2).
Febrile Drug Reaction	• Fever higher than 104°F • Fever complicated by rigors, hypotension, dehydration, or renal failure	Either • Permanently discontinue TAFINLAR Or • Withhold TAFINLAR until adverse reaction resolves. Then resume TAFINLAR at a reduced dose level (see Table 2).
Other	• Intolerable Grade 2 Adverse Reactions • Any Grade 3 Adverse Reactions	Withhold TAFINLAR until adverse reaction resolves to Grade 1 or less. Then resume TAFINLAR at a reduced dose level (see Table 2).
	• First occurrence of Any Grade 4 Adverse Reaction	Either • Permanently discontinue TAFINLAR Or • Withhold TAFINLAR until adverse reaction resolves to Grade 1 or less. Then resume TAFINLAR at a reduced dose level (see Table 2).
	• Recurrent Grade 4 Adverse Reaction • Intolerable Grade 2 or Any Grade 3 or 4 Adverse Reaction on TAFINLAR 50 mg twice daily	Permanently discontinue TAFINLAR.

a Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Table 2. Recommended TAFINLAR Dose Reductions
Dose Reductions	Dose and Schedule
First dose reduction	100 mg orally twice daily
Second dose reduction	75 mg orally twice daily
Third dose reduction	50 mg orally twice daily
If unable to tolerate 50 mg twice daily	Discontinue TAFINLAR

3 DOSAGE FORMS AND STRENGTHS

50 mg Capsules: Dark red capsule imprinted with ‘GS TEW’ and ‘50 mg’.

75 mg Capsules: Dark pink capsule imprinted with ‘GS LHF’ and ‘75 mg’.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 New Primary Cutaneous Malignancies

TAFINLAR results in an increased incidence of cutaneous squamous cell carcinoma, keratoacanthoma, and melanoma. In Trial 1, cutaneous squamous cell carcinomas and keratoacanthomas (cuSCC) occurred in 7% (14/187) of patients treated with TAFINLAR and in none of the patients treated with dacarbazine. Across clinical trials of TAFINLAR (n = 586), the incidence of cuSCC was 11%. The median time to first cuSCC was 9 weeks (range: 1 to 53 weeks). Of those patients who developed a cuSCC, approximately 33% developed one or more cuSCC with continued TAFINLAR. The median time between diagnosis of the first cuSCC and the second cuSCC was 6 weeks.

In Trial 1, the incidence of new primary malignant melanomas was 2% (3/187) for patients receiving TAFINLAR while no chemotherapy-treated patient was diagnosed with new primary malignant melanoma.

Perform dermatologic eva luations prior to initiation of TAFINLAR, every 2 months while on therapy, and for up to 6 months following discontinuation of TAFINLAR.

5.2 Tumor Promotion in BRAF Wild-Type Melanoma

In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells which are exposed to BRAF inhibitors. Confirm evidence of BRAF V600E mutation status prior to initiation of TAFINLAR [see Indications and Usage (1) and Dosage and Administration (2.1)].

5.3 Serious Febrile Drug Reactions

In Trial 1, serious febrile drug reactions, defined as serious cases of fever or fever of any severity accompanied by hypotension, rigors or chills, dehydration, or renal failure in the absence of another identifiable cause (e.g., infection) occurred in 3.7% (7/187) of patients treated with TAFINLAR and in none of the patients treated with dacarbazine. The incidence of fever (serious and non-serious) was 28% in patients treated with TAFINLAR and 10% in patients treated with dacarbazine. In patients treated with TAFINLAR, the median time to initial onset of fever (any severity) was 11 days (range: 1 to 202 days) and the median duration of fever was 3 days (range: 1 to 129 days).

Withhold TAFINLAR for fever of 101.3ºF or greater or for any serious febrile drug reaction and eva luate for signs and symptoms of infection. Refer to Table 1 for recommended dose modifications for adverse reactions [see Dosage and Administration (2.3)]. Prophylaxis with antipyretics may be required when resuming TAFINLAR.

5.4 Hyperglycemia

Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral hypoglycemic agent therapy can occur with TAFINLAR. In Trial 1, five of 12 patients with a history of diabetes required more intensive hypoglycemic therapy while taking TAFINLAR. The incidence of Grade 3 hyperglycemia based on laboratory values was 6% (12/187) in patients treated with TAFINLAR compared to none of the dacarbazine-treated patients.

Monitor serum glucose levels as clinically appropriate during treatment with TAFINLAR in patients with pre-existing diabetes or hyperglycemia. Advise patients to report symptoms of severe hyperglycemia such as excessive thirst or any increase in the volume or frequency of urination.

5.5 Uveitis and Iritis

Uveitis (including iritis) occurred in 1% (6/586) of patients treated with TAFINLAR across clinical trials. Symptomatic treatment employed in clinical trials included steroid and mydriatic ophthalmic drops. Monitor patients for visual signs and symptoms of uveitis (e.g., change in vision, photophobia, and eye pain).

5.6 Glucose-6-Phosphate Dehydrogenase Deficiency

TAFINLAR, which contains a sulfonamide moiety, confers a potential risk of hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Closely observe patients with G6PD deficiency for signs of hemolytic anemia.

5.7 Embryofetal Toxicity

Based on its mechanism of action, TAFINLAR can cause fetal harm when administered to a pregnant woman. Dabrafenib was teratogenic and embryotoxic in rats at doses three times greater than the human exposure at the recommended clinical dose. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)].

Advise female patients of reproductive potential to use a highly effective non-hormonal method of contraception during treatment and for 4 weeks after treatment since TAFINLAR can render hormonal contraceptives ineffective. Advise patients to contact their healthcare provider if they become pregnant, or if pregnancy is suspected, while taking TAFINLAR [see Drug Interactions (7.2), Use in Specific Populations (8.6)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in another section of the label.

•: New Primary Cutaneous Malignancies [see Warnings and Precautions (5.1)]
•: Tumor Promotion in BRAF Wild-Type Melanoma [see Warnings and Precautions (5.2)]
•: Serious Febrile Drug Reactions [see Warnings and Precautions (5.3)]
•: Hyperglycemia [see Warnings and Precautions (5.4)]
•: Uveitis and Iritis [see Warnings and Precautions (5.5)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of TAFINLAR was eva luated in 586 patients with BRAF V600 mutation-positive unresectable or metastatic melanoma, previously treated or untreated, who received TAFINLAR 150 mg orally twice daily as monotherapy until disease progression or unacceptable toxicity, including 181 patients treated for at least 6 months and 86 additional patients treated for more than 12 months. TAFINLAR was studied in open-label, single-arm trials and in an open-label, randomized, active-controlled trial. The median daily dose of TAFINLAR was 300 mg (range: 118 to 300 mg).

Table 3 and Table 4 present adverse drug reactions and laboratory abnormalities identified from analyses of Trial 1 [see Clinical Studies (14)]. Trial 1, a multi-center, international, open-label, randomized (3:1), controlled trial allocated 250 patients with unresectable or metastatic BRAF V600E mutation-positive melanoma to receive TAFINLAR 150 mg orally twice daily (n = 187) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 63). The trial excluded patients with abnormal left ventricular ejection fraction or cardiac valve morphology (≥Grade 2), corrected QT interval ≥480 milliseconds on electrocardiogram, or a known history of glucose-6-phosphate dehydrogenase deficiency. The median duration on treatment was 4.9 months for patients treated with TAFINLAR and 2.8 months for dacarbazine-treated patients. The population exposed to TAFINLAR was 60% male, 99% white, and had a median age of 53 years.

The most commonly occurring adverse reactions (≥20%) in patients treated with TAFINLAR were, in order of decreasing frequency: hyperkeratosis, headache, pyrexia, arthralgia, papilloma, alopecia, and palmar-plantar erythrodysesthesia syndrome (PPES).

The incidence of adverse events resulting in permanent discontinuation of study medication in Trial 1 was 3% for patients treated with TAFINLAR and 3% for patients treated with dacarbazine. The most frequent (≥2%) adverse reactions leading to dose reduction of TAFINLAR were pyrexia (9%), PPES (3%), chills (3%), fatigue (2%), and headache (2%).

Table 3. Selected Common Adverse Reactions Occurring in ≥10% (All Grades) or ≥2% (Grades 3 or 4) of Patients Treated with TAFINLARa
	TAFINLAR N = 187		Dacarbazine N = 59
Primary System Organ Class Preferred Term	All Grades (%)	Grades 3 and 4b (%)	All Grades (%)	Grades 3 and 4 (%)
Skin and subcutaneous tissue disorders
Hyperkeratosis	37	1	0	0
Alopecia	22	NA f	2	NA f
Palmar-plantar erythrodysesthesia syndrome	20	2	2	0
Rash	17	0	0	0
Nervous system disorders
Headache	32	0	8	0
General disorders and administration site conditions
Pyrexia	28	3	10	0
Musculoskeletal and connective tissue disorders
Arthralgia	27	1	2	0
Back pain	12	3	7	0
Myalgia	11	0	0	0
Neoplasms benign, malignant and unspecified (including cysts and polyps)
Papillomac	27	0	2	0
cuSCCd, e	7	4	0	0
Gastrointestinal disorders
Constipation	11	2	14	0
Respiratory, thoracic, and mediastinal disorders
Cough	12	0	5	0
Infections and infestations
Nasopharyngitis	10	0	3	0

a Adverse drug reactions, reported using MedDRA and graded using CTCAE version 4.0 for assessment of toxicity.

b Grade 4 adverse reactions limited to hyperkeratosis (n = 1) and constipation (n = 1).

c Includes skin papilloma and papilloma.

d Includes squamous cell carcinoma of the skin and keratoacanthoma.

e Cases of cutaneous squamous cell carcinoma were required to be reported as Grade 3 per protocol.

f NA = not applicable

Table 4. Incidence of Laboratory Abnormalities Increased from Baseline Occurring at a Higher Incidence in Patients Treated with TAFINLAR in Trial 1 [Between Arm Difference of ≥5% (All Grades) or ≥2% (Grades 3 or 4)]
	Dabrafenib N = 187		DTIC N = 59
	All Grades (%)	Grades 3 and 4 (%)	All Grades (%)	Grades 3 and 4 (%)
Hyperglycemia	50	6	43	0
Hypophosphatemia	37	6a	14	2
Increased Alkaline phosphatase	19	0	14	2
Hyponatremia	8	2	3	0